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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia
American Journal of Human Genetics, Volume 92, No. 2, Year 2013
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Description
Spastic paraplegia 46 refers to a locus mapped to chromosome 9 that accounts for a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP). With next-generation sequencing in three independent families, we identified four different mutations in GBA2 (three truncating variants and one missense variant), which were found to cosegregate with the disease and were absent in controls. GBA2 encodes a microsomal nonlysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide to free glucose and ceramide and the hydrolysis of bile acid 3-O-glucosides. The missense variant was also found at the homozygous state in a simplex subject in whom no residual glucocerebrosidase activity of GBA2 could be evidenced in blood cells, opening the way to a possible measurement of this enzyme activity in clinical practice. The overall phenotype was a complex HSP with mental impairment, cataract, and hypogonadism in males associated with various degrees of corpus callosum and cerebellar atrophy on brain imaging. Antisense morpholino oligonucleotides targeting the zebrafish GBA2 orthologous gene led to abnormal motor behavior and axonal shortening/branching of motoneurons that were rescued by the human wild-type mRNA but not by applying the same mRNA containing the missense mutation. This study highlights the role of ceramide metabolism in HSP pathology. © 2013 The American Society of Human Genetics.
Authors & Co-Authors
Martin, Elodie M.
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Inserm
France, Paris
Cnrs Centre National de la Recherche Scientifique
France, Paris
Hôpital Universitaire Pitié Salpêtrière
Schüle, Rebecca
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Smets, Katrien
Belgium, Antwerpen
Universiteit Antwerpen
Belgium, Edegem
Universitair Ziekenhuis Antwerpen
Belgium, Wilrijk
Instituut Born-bunge
Rastetter, Agnès
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Inserm
France, Paris
Cnrs Centre National de la Recherche Scientifique
France, Paris
Hôpital Universitaire Pitié Salpêtrière
Boukhris, Amir
Tunisia, Sfax
Chu Habib Bourguiba
Tunisia, Sfax
Faculty of Medicine of Sfax
Loureiro, José Leal
Portugal, Porto
Instituto de Biologia Molecular e Celular
Portugal, Aveiro
Centro Hospitalar Entre Douro e Vouga
González, Michael Anthony
United States, Miami
University of Miami Leonard M. Miller School of Medicine
Mundwiller, Emeline
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Inserm
France, Paris
Cnrs Centre National de la Recherche Scientifique
France, Paris
Hôpital Universitaire Pitié Salpêtrière
Deconinck, Tine
Belgium, Antwerpen
Universiteit Antwerpen
Belgium, Wilrijk
Instituut Born-bunge
Wessner, Marc
France, Evry
Genoscope - Centre National de Séquençage
Jornea, Ludmila
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Inserm
France, Paris
Cnrs Centre National de la Recherche Scientifique
Oteyza, Andrés Caballero
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Dürr, Alexandra
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Inserm
France, Paris
Cnrs Centre National de la Recherche Scientifique
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Martín, Jean Jacques R.
Belgium, Wilrijk
Instituut Born-bunge
Schöls, Ludger
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Mhiri, Chokri
Tunisia, Sfax
Chu Habib Bourguiba
Lamari, Foudil
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Züchner, Stephan L.
United States, Miami
University of Miami Leonard M. Miller School of Medicine
de Jonghe, Peter
Belgium, Antwerpen
Universiteit Antwerpen
Belgium, Edegem
Universitair Ziekenhuis Antwerpen
Belgium, Wilrijk
Instituut Born-bunge
Kabashi, Edor
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Inserm
France, Paris
Cnrs Centre National de la Recherche Scientifique
Brice, Alexis
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Inserm
France, Paris
Cnrs Centre National de la Recherche Scientifique
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Stévanin, Giovanni
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Inserm
France, Paris
Cnrs Centre National de la Recherche Scientifique
France, Paris
Hôpital Universitaire Pitié Salpêtrière
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Statistics
Citations: 150
Authors: 22
Affiliations: 16
Identifiers
Doi:
10.1016/j.ajhg.2012.11.021
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Cancer
Genetics And Genomics